Clinical Trials in Medical Retina

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Article initiated by:

Francesc March de Ribot, MD, PhD

All contributors:

Leo A. Kim, MD, PhD, Koushik Tripathy, MD (AIIMS), Francesc March de Ribot, MD, PhD, Aparna Bose, MS (AMU)

Assigned editor:

Koushik Tripathy, MD (AIIMS)

Review:

Assigned status Update Pending

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Contributing Editors:	add

AREDS (Age- Related Eye Disease Study)

Objectives

• Assess the clinical course, prognosis, and risk factors of Age-related macular degeneration (ARMD )and cataract

• Evaluate the effects of nutrients, including high-dose antioxidants, omega-3 fatty acids, and zinc, on the progression of AMD, cataract, and related vision loss

Design

AREDS included 4,757 participants, ages 55-80 years, with ARMD ranging from none in either eye to advanced ARMD in one eye but good vision (at least 20/30) in the other eye. The participants were enrolled at 11 clinics nationwide and their clinical progression was followed for 5 years. They were categorized into five groups based on the stage of AMD at presentation.

Category	Description
I- No ARMD	Few small or no drusen
II- Early ARMD	Many small drusen or a few medium-sized drusen in one or both eyes
III- Intermediate ARMD	Many medium-sized drusen or one or more large drusen in one or both eyes
IV-Advanced ARMD	In one eye only, either a breakdown of light-sensitive cells and supporting tissue in the central retinal area (advanced dry form) or abnormal and fragile blood vessels under the retina (wet form)

The participants in each category were randomly selected to receive daily oral tablets for one of four treatments:

1. antioxidant formulation (see below) and zinc (80mg) + copper (2mg)
2. zinc (80mg) + copper (2mg)
3. antioxidant formulation [vitamin C (500 mg) + vitamin E (400 IU) +beta-carotene (15 mg)]
4. a placebo (a pill with no active ingredients)

Main outcome measures

Risk reduction for each formulation, compared to placebo.

Results

AREDS scientists found that people at high risk for developing advanced AMD—those with intermediate AMD, and those with advanced AMD in one eye only—reduced their risk of developing advanced by about 25 percent when treated with the combination of antioxidants and zinc + copper (final AREDS formula).  The AREDS formula also reduced the risk of central vision loss by 19% in the same group. None of the formulations decreased cataract risk.

AREDS 2

Objectives

• To test if adding omega-3 fatty acids or lutein + zeaxanthin would make the AREDS formula more effective.
• The effect of eliminating beta-carotene, which in some studies increased lung cancer risk in smokers.
• Effect of lowering the zinc dose.

Design

AREDS2 investigators enrolled 4,203 participants, ages 50-85. AREDS2 included only people with intermediate AMD in both eyes or intermediate AMD in one eye and advanced AMD in the other eye. AREDS2 excluded people without AMD or with early AMD because AREDS data showed no benefit for these individuals.

Primary randomization: AREDS2 investigators randomly assigned participants to one of the following groups:

1. Omega-3 fatty acids (350 mg docosahexanoic acid + 650 mg eicosapentanoic acid)
2. Lutein (10 mg) + zeaxanthin (2 mg)
3. Lutein + zeaxanthin and omega-3 fatty acids
4. Placebo

Secondary randomization: Additionally, 3549 AREDS2 participants were randomized to take one of the following:

1. AREDS formula
2. AREDS formula minus beta-carotene
3. AREDS formula with low (25 mg) zinc
4. AREDS formula minus beta-carotene and with low (25 mg) zinc.

The remaining participants were not randomized and continued to take the AREDS formula.

Results

In the AREDS2 trial, adding omega-3 fatty acids or lutein + zeaxanthin to the AREDS formula had no additional overall effect on the risk of advanced AMD. However, AREDS2 participants who took antioxidants minus beta-carotene but with lutein + zeaxanthin (AREDS2 formula) had an incremental increase in benefit, compared to those who took the AREDS formula.

AREDS2 participants who were former smokers who took a formulation with beta-carotene had a higher incidence of lung cancer. The investigators found no significant changes in the effectiveness of the formulation when they removed beta-carotene or reduced the zinc dose.

Adding omega-3 fatty acids or lutein + zeaxanthin to antioxidants plus zinc (AREDS formula) had no overall effect on the need for cataract surgery.

ANCHOR (Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration)

Objective

The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV.

Design

Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial.

Participants

Patients with predominantly classic, sub-foveal CNV not previously treated with PDT or antiangiogenic drugs.

Intervention

Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA).

Main outcome measures

The primary intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored.

Results

Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT).

Conclusions

In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low.

MARINA

Objective

To evaluate the efficacy of Ranibizumab for the treatment of neovascular age-related macular degeneration.

Design

In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.

Result

We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.

Conclusions

Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration.

VIEW 1 & VIEW 2

Objective

To compare efficacy and safety of monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab for the treatment of neovascular AMD.

Design

Double-masked, multicenter, parallel-group, active-controlled, randomized, phase-3 trials.

Participants

Patients (n = 2419) [ VIEW 1: n=1217 from USA & Canada ; VIEW 2: n=1240 from Europe, Asia Pacific, Japan & Latin America] with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD.

Intervention

Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).

Main outcome measures

The primary endpoint was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key endpoints included change in best-corrected visual acuity (BCVA) and anatomic measures.

Results

All aflibercept groups were non-inferior and clinically equivalent to monthly ranibizumab for the primary endpoint (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups.

Conclusions

Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every 2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.

CATT (Comparison of Age-related Macular Degeneration Treatment Trial)

Purpose

To describe outcomes 5 years after initiation of treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD).

Design

Cohort study

Participants

Patients enrolled in the Comparison of AMD Treatments Trials (CATT).

Methods

Patients were randomly assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At approximately 5 years, patients were recalled for examination.

Main Outcome Measures

Visual acuity (VA) and morphologic retinal features.

Results

VA was obtained for 647 (71%) of 914 living patients with an average follow-up time of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments in the study eye was 15.4. Most (60%) patients were treated ≥1 times with a drug other than their randomly assigned drug. At the 5-year visit, 50% of study eyes had VA 20/40 or better, and 20% had VA 20/200 or worse. The mean change in VA was −3 letters from baseline and −11 letters from 2 years. Among 467 eyes with fluorescein angiography, the mean total lesion area was 12.9 mm2, a mean of 4.8 mm2 larger than at 2 years. Geographic atrophy was present in 213 (41%) of 515 gradable eyes and was subfoveal in 85 (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm; a decrease of 182 μm from baseline and 20 μm from 2 years. An abnormally thin retina at the foveal center (<120 μm) was present in 36%. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (−4 letters; p=0.008). Otherwise, there were no statistically significant differences in VA or morphological outcomes between drug or regimen groups.

Conclusion

Vision gains during the first 2 years of the trial were not maintained at 5 years. However, 50% of eyes had VA 20/40 or better, confirming anti-VEGF therapy as a major long-term therapeutic advance for neovascular AMD.

IVAN (Inhibit vascular endothelial growth factor (VEGF) in age-related choroidal neovascularisation)

Objective

To compare the efficacy and safety of ranibizumab versus bevacizumab (monthly or as-needed treatment regimens) in the treatment of neovascular age-related macular degeneration.

Study Design

Multicenter, factorial, noninferiority, randomized, treatment-controlled trial (UK-based study)

Participants

Major Inclusion criteria:

≧ 50 years old

Treatment naive neovascular AMD (nAMD)- confirmed by fluorescein angiography

Best corrected visual acuity (BCVA) > 25 letters on ETDRS

Sub-foveal (within 200 um) choroidal neovascular (CNV) lesion or extrafoveal CNV with foveal sub-retinal fluid or subfoveal serous pigment epithelial detachment (PED)

Major exclusion criteria:

CNV lesion comprising >50% fibrosis or blood

Greatest linear diameter of CNV lesion > 6000 um

Randomization

Randomized 1:1:1 to

(a) Ranibizumab (0.5 mg) monthly

(b) Ranibizumab (0.5 mg) as-needed

(c) Bevacizumab (1.25 mg) monthly

(d) Bevacizumab (1.25 mg) as-needed

All participants attended monthly visits with clinical examination, optical coherence tomography (OCT), and funds photography. All patients were treated at visits 0, 1, and 2. The continuous arm was treated monthly thereafter. The as-needed group were not treated unless they met pre-specified clinical and OCT criteria for active disease. If re-treatment was-needed, then a cycle of 3 monthly doses were required. Subjects and assessment teams were masked; treatment teams were unmasked (14 out of 23 sites).

Amendment later allowed for PDT for any subtype of CNVM if lesion > 4 DA and accompanied by loss of 20 letters of vision.

Re-Treatment Criteria:

OCT Findings: presence of subretinal fluid, increasing intraretinal fluid, fresh hemorrhage

VA Findings: A visual acuity drop in > 10 letters if OCT parameters were equivocal

FA Findings: >25% fluorescein leakage of the lesion size or expansion of the CNV lesion if VA or OCT did not qualify

Distance BCVA at 1 year—measured by ETDRS

Results ( 12 months):

Study population

610 patients – ranibizumab monthly (n=157), ranibizumab as-needed (n=155), monthly bevacizumab (n=149), as-needed (n=138)

Primary Outcome: Distance BCVA at 1 year

Inconclusive by drug type (neither noninferior or nor equivalent)- did not reach 3.5 letter difference requirement to be classified as noninferior (-2.00 letters ranibiz, 95% CI, -4.04-0.06)

Monthly versus as-needed treatment were equivalent

Secondary Outcomes:

VA: Near visual acuity worse by 8% in bevacizumab group, but no difference by treatment regimen

OCT: Mean foveal thickness: 9% less for monthly group; no difference by drug type

Statistically more FA leakage (36% vs 24%, p=0.002) and larger lesion size in as- needed group

Lower serum VEGF concentrations in bevacizumab group and monthly group

No difference in contrast sensitivity, reading index, EQ-SD score for drug type or treatment regimen

Cost (greatest to least): Monthly ranibizumab most costly (9656 pounds)—>as-needed ranibizumab (3258 pounds) -->Bevacizumab monthly or as-needed (least costly)

No statistical difference in cost of monthly bevacizumab versus as-needed bevacizumab

Adverse events

No difference in mortality or serious systemic adverse events by drug type or treatment regimen

Higher arteriothrombotic or heart failure events in ranibizumab group compared to bevacizumab (2.9% vs 0.7%; OR 0.23, p = 0.003); no difference in treatment regimens

Conclusion

There were inconclusive results when comparing VA between ranibizumab and bevacizumab at 1 year

There was no difference in VA based on treatment regimen (monthly or as-needed) at 1 year

There were overall similar safety and efficacy outcomes, with the exception of a small statistical increase in arteriothrombotic event or heart failure in the ranibizumab group at 1 year.

GEFAL

Objective

To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD).

Design

Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters.

Participants

Patients aged ≥50 years were eligible if they presented with sub-foveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA).

Methods

Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up.

Main outcome measures

Mean change in visual acuity at 1 year.

Results

Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups.

Conclusions

Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies.

LUCAS (Lucentis Compared to Avastin Study)

Purpose

To compare the efficacy and safety of bevacizumab versus ranibizumab when administered according to a treat-and-extend protocol for the treatment of neovascular age-related macular degeneration (AMD).

Design

Multicenter, randomized, noninferiority trial with a noninferiority limit of 5 letters.

Participants

Patients aged ≥ 50 years with previously untreated neovascular AMD in 1 eye and best-corrected visual acuity (BCVA) between 20/25 and 20/320.

Methods

Patients were randomly assigned to receive ranibizumab 0.5 mg or bevacizumab 1.25 mg intravitreal injections. Monthly injections were given until inactive disease was achieved. The patients were then followed with a gradual extension of treatment interval by 2 weeks at a time up to a maximum of 12 weeks. If signs of recurrent disease appeared, the treatment interval was shortened by 2 weeks at a time.

Main outcome measures

Change in visual acuity at 1 year.

Results

Between March 2009 and July 2012, 441 patients were randomized at 10 ophthalmological centers in Norway. The 1-year visit was completed by 371 patients. In the per protocol analysis at 1 year, bevacizumab was equivalent to ranibizumab, with 7.9 and 8.2 mean letters gained, respectively (95% confidence interval [CI] of mean difference, -2.4 to 2.9; P = 0.845). The intention-to-treat analysis was concordant. There was no significant difference in measured central retinal thickness (CRT), with a mean decrease of -112 μm for bevacizumab and -120 μm for ranibizumab (95% CI of mean difference, -13 to 28; P = 0.460). There was a statistically significant difference (P = 0.001) between the drugs regarding the number of treatments: 8.9 for bevacizumab and 8.0 for ranibizumab. There were fewer arteriothrombotic events in the bevacizumab group (1.4%) than in the ranibizumab group (4.5%) (P = 0.050) and significantly more cardiac events in the ranibizumab group (P = 0.036). However, patients treated with ranibizumab more often had a history of myocardial infarction (P = 0.021).

Conclusions

Bevacizumab and ranibizumab had equivalent effects on visual acuity at 1 year when administered according to a treat-and-extend protocol. The visual acuity results at 1 year were comparable to those of other clinical trials with monthly treatment. The numbers of serious adverse events were small.

BRAMD

Purpose

To compare the effectiveness of bevacizumab and ranibizumab in the treatment of exudative age-related macular degeneration (AMD).

Design

Multicentre, randomized, controlled, double-masked clinical trial in 327 patients. The non-inferiority margin was 4 letters.

Patients

Patients ≥ 60 years of age with primary or recurrent sub- or juxtafoveal choroidal neovascularization (CNV) secondary to AMD with a total area of CNV < 12 disc areas and a best corrected visual acuity (BCVA) score between 20 and 78 letters on an EDTRS like chart in the study eye.

Methods

Monthly intravitreal injections with 1.25 mg bevacizumab or 0.5 mg ranibizumab were given during one year. Intention to treat with last observation carried forward analysis was performed.

Main Outcome Measures

Primary outcome was the change in BCVA in the study eye from baseline to 12 months.

Results

The mean gain in BCVA was 5.1 (±14.1) letters in the bevacizumab group (n = 161) and 6.4 (±12.2) letters in the ranibizumab group (n = 166) (p = 0.37). The lower limit of the 95% confidence interval of the difference in BCVA gain was 3.72. The response to bevacizumab was more varied; 24% of patients showed a gain of ≥15 letters, 11% a loss of ≥15 letters and 65% a gain or loss < 15 letters compared to 19%, 5% and 76% respectively for ranibizumab (p = 0.038). No significant differences in absolute CRT and CRT change (p = 0.13) or in the presence of subretinal or intraretinal fluid (p = 0.14 and 0.10, respectively) were observed. However, the presence of any fluid on SD-OCT (subretinal and/or intraretinal) differed significantly (p = 0.020), with definite fluid on SD-OCT in 45% of the patients for bevacizumab versus 31% for ranibizumab. The occurrence of serious adverse events and adverse events was similar, with 34 SAEs and 256 AEs in the bevacizumab group and 37 SAEs and 299 AEs in the ranibizumab group (p = 0.87 and p = 0.48, respectively).

Conclusions

Bevacizumab was not inferior to ranibizumab. The response to bevacizumab was more varied with higher percentages of both gainers and losers and more frequently observed retinal fluid on SD-OCT at 12 months when compared to the ranibizumab group.

MANTA (Multicenter Anti-VEGF Trial in Austria)

Aim

The current accepted standard treatment for neovascular age-related macular degeneration (AMD) consists of anti-vascular endothelial growth factor agents including ranibizumab and bevacizumab. The aim of the study was to examine whether bevacizumab is inferior to ranibizumab with respect to maintaining/improving visual acuity.

Methods

In this prospective randomized parallel group multicenter trial patients aged more than 50 years with treatment naive nAMD were included at 10 Austrian centers. Patients were randomized to treatment either with 0.5 mg ranibizumab or 1.25 mg bevacizumab. Both groups received three initial monthly injections and thereafter monthly evaluation of visual acuity and the activity of the lesion. Re-treatment was scheduled as needed. Outcome measures were early treatment of diabetic retinopathy visual acuity, retinal thickness, lesion size and safety evaluation.

Results

A total of 321 patients were recruited of which four had to be excluded due to different reasons. Of the 317 remaining patients 154 were randomised into the bevacizumab group and 163 into the ranibizumab group. At month 12, there was a mean increase of early treatment of diabetic retinopathy visual acuity of 4.9 letters in the bevacizumab and 4.1 letters in the ranibizumab group (p=0.78). Furthermore, there were no significant differences in the decrease of retinal thickness, change of lesion size and number of adverse events between the groups.

Conclusions

Bevacizumab was equivalent to ranibizumab for visual acuity at all time points over 1 year. There was no significant difference of decrease of retinal thickness or number of adverse events.

DRS (Diabetic Retinopathy Study)

Study Question

Does PRP (argon or xenon arc) prevent severe vision loss in eyes with diabetic retinopathy?

Participants

Patients were included in the study if they had PDR in at least one eye or severe NPDR in both eyes, and had VA of 20/100 or better in each eye.

Severe NPDR was defined as the presence at least 3 of the following:

1.     Cotton wool spots

2.     Venous beading

3.     Intraretinal microvascular abnormalities (IRMA) in at least 2 contiguous overlapping photographic fields

4.     Moderate-to-severe retinal hemorrhages and/or MA’s

Patients were excluded if they had undergone previous PRP or had a macula-threatening TRD.

Design

This was a randomized, prospective multicenter clinical trial.  1742 study subjects were enrolled.  One eye from each subject was randomly assigned to PRP and the other eye assigned to no PRP.  The PRP eyes were randomized to either argon blue-green laser (800-1600, 500 micron spots) or xenon arc (200-400, 4.5 degree spots).

The primary outcome measure was severe vision loss, defined as VA < 5/200 on two consecutive follow-up exams, 4 months apart.

Results

PRP reduced the risk of severe vision loss by at least 50% as compared to untreated control eyes.   The greatest benefit was seen in eyes with high-risk PDR.  Study follow-up was over 5 years.

High-risk PDR was defined as any one of the following:

1.     NVD ≥ 1/3 disc area

2.     Any NVD with vitreous hemorrhage

3.     NVE ≥ ½ disc area with vitreous hemorrhage

High-risk PDR was also defined as three or more of the following high-risk characteristics (HRC’s):

1.     Presence of vitreous hemorrhage or pre-retinal hemorrhage

2.     Presence of any active neovascularization

3.     Location of neovascularization on or within one disc diameter of the optic disc

4.     NVD > 1/3 disc area or NVE > ½ disc area

Eyes with high-risk PDR had significantly greater risk of severe visual loss and demonstrated the greatest benefit from PDR.

No clear benefit was demonstrated for PRP in eyes with severe NPDR or in eyes with PDR without high-risk characteristics.

Risks of treatment include small reductions in visual acuity or visual field.  Harmful effects of argon laser treatment were less than those seen with xenon arc treatment.  In the argon laser treatment group, a decrease in VA of 1 or more lines was seen in 11% of eyes; visual field loss was seen in 5%.

Conclusions

PRP reduces the risk of severe vision loss compared with no treatment in eyes with high-risk PDR.

Eyes with high-risk PDR should receive prompt treatment with PRP.  Eyes with two or fewer high risk characteristics (HRC’s) still benefit from PRP, but the benefit is small and risks of treatment may outweigh the benefits.  However, consider earlier treatment with PRP for older-onset diabetic patients.

ETDRS (Early Treatment Diabetic Retinopathy Study)

Purpose

The efficacy of argon laser photocoagulation and aspirin in diabetic retinopathy.

Objective

The ETDRS trial was designed to assess:

• the efficacy of argon laser photocoagulation (both macular and scatter laser) and aspirin therapy in deterring the progression of early DR into more advanced DR
• the best time to initiate photocoagulation treatment where necessary
• the natural history and risk factors for progression of diabetic retinopathy

Design

Multi-centre randomised controlled trial.

Recruitment

• Commenced December 1979
• Completed June 1985
• 3711 patients
• 22 centres
• Follow-up ended: 1989

Participants

Inclusion Criteria

• Age 18 - 70 years
• Male and Female
• Moderate or severe nonproliferative diabetic retinopathy or mild proliferative retinopathy in both eyes
• No previous photocoagulation treatment
• Visual acuity of 20/40 or better (20/200 or better if macular edema is present)

Methods

All patients were assigned to either aspirin treatment or a placebo during the course of the study.

Additionally, one eye of each patient was assigned to immediate laser. Two types of laser were analysed in the study: focal macular laser and peripheral scatter laser. Eyes selected for immediate treatment received one of four different combinations of focal and scatter treatment. By varying the amount of scatter treatment given and the time of initiation of focal treatment for macular edema, the study investigators hoped to find the best possible early treatment strategy.

The other eye not selected for immediate laser was carefully followed up and evaluated every four months and received scatter laser only if it progressed to high-risk pre-proliferative retinopathy.

Results

Aspirin

Aspirin use did not affect the progression of retinopathy to the high-risk proliferative stage in eyes assigned to deferral of photocoagulation. However, aspirin did not increase the risk of vitreous hemorrhage, did not affect vision, and was associated with a decreased risk of cardiovascular disease. The study therefore concluded that for patients with mild to severe nonproliferative or early proliferative diabetic retinopathy, it is likely that aspirin has no clinically important beneficial effect on the progression of retinopathy. However, the study also showed no clinically important harmful effects for diabetic patients with retinopathy and therefore no ocular contraindications to aspirin use when required for cardiovascular disease or other medical indications.

Focal Macular Laser

The ETDRS demonstrated that focal macular laser reduced the risk of moderate vision loss (defined as a doubling of the visual angle) by up to 50% in eyes with "clinically significant macular oedema."  Clinically significant macular oedema was defined as:

• Retinal thickening at or within 500 microns or 1/3 disc diameter of center of macula
• Hard exudates at or within 500 microns of the center of the macula with adjacent retinal thickening.
• Retinal thickening GREATER than 1 disc diameter in size which is within 1 disc diameter from the center of the macula

There was also an increase of moderate visual gain in eyes receiving focal treatment as well as a decrease in the amount of retinal thickening.  The recommendation was that eyes with clinically significant macular oedema should be considered for focal photocoagulation.

Scatter PRP

The ETDRS study demonstrated a statistically significant reduction in severe visual loss in eyes receiving early scatter laser treatment, especially for those patients with non-insulin-dependent diabetes mellitus (NIDDM). However, the reduction was small and the risk was low in the deferral group. The recommendation was that scatter treatment should be deferred for eyes with mild to moderate nonproliferative diabetic retinopathy. As the retinopathy progresses to the severe nonproliferative or early proliferative stage, scatter treatment should be considered, especially for patients with NIDDM. Scatter photocoagulation should be performed for virtually all eyes with high-risk proliferative retinopathy. Finally, early vitrectomy should be considered for advanced active proliferative diabetic retinopathy, and most importantly, all patients with diabetic retinopathy should receive careful followup.

Conclusion

The ETDRS study was a landmark trial in that it demonstrated conclusively the benefit of focal macular laser in the treatment of diabetic macular oedema.  It also set out the criteria for treatment of "clinically significant macular oedema" - criteria which are still used today in determining which patients should be treated with macular laser.

The ETDRS study was also crucial in determining that scatter laser PRP reduces the risk of disease progression and vision loss - but that scatter treatment can be delayed until the development of severe non-proliferative or early proliferative stage retinopathy.

Finally, the ETDRS study established that aspirin has no role in preventing the progression of diabetic retinopathy, but that equally, it is not contraindicated and can be used where other cardiovascular indications require.

In all these respects, the ETDRS was an historical study, and its findings still influence the management of diabetic retinopathy today.

DCCT (Diabetes Control and Complications Trial)

Purpose

The role of intensive glycaemic control on diabetic retinopathy in T1 DM

Design

Randomised controlled trial

Participants

1441 Type 1 Diabetics

Randomization

The DCCT randomized 1441 patients with Type 1 Diabetes to receive intensive glycemic or conventional therapy.

Results

Over 6.5 years of follow-up, intensive treatment (median HbA1c, 7.2%) reduced the incidence of diabetic retinopathy by 76% and progression of diabetic retinopathy by 54%, as compared with conventional treatment.

Long-term observational DCCT data showed that despite gradual equalization of HbA1c values after study termination, the rate of diabetic retinopathy progression in the former intensively treated group remained significantly lower than in the former conventional group (‘metabolic memory') emphasizing the importance of instituting tight glycemic control early in the course of diabetes.

Tight glycemic control has two clinically important adverse effects. First, there is risk of early worsening of diabetic retinopathy. In the DCCT, this condition occurred in 13.1% of the intensive versus 7.6% of the conventional treatment group. However, this effect was reversed by 18 months, and no case of early worsening resulted in serious visual loss.

In the DCCT, the long-term benefits of intensive insulin therapy greatly outweighed the risks of early worsening. Therefore ophthalmoscopic monitoring before initiation of intensive treatment and at 3-month intervals for 6-12 months thereafter seems appropriate when intensive treatment is initiated in patients with long-standing poor glycemic control, particularly if retinopathy is at, or past, the moderate non-proliferative stage.

In patients whose retinopathy is already approaching the high-risk stage, it may be prudent to delay the initiation of intensive treatment until photocoagulation can be completed, particularly if HbA1c is high. Second, tight glycemic control was associated with more frequent severe hypoglycemic episodes compared with the conventional group.

Conclusion

The DCCT was a landmark trial in establishing that tight control of blood sugars in Type 1 diabetics can reduce the incidence of retinopathy and slow progression in those with established retinopathy.

DRCR protocols

Protocol W 2021

Objectives

The goal was to determine the efficacy of intravitreous aflibercept injections compared to sham in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR. The role of anti-VEGF in managing NPDR without center-involved diabetic macular edema (CI-DME) has not been established.

Design

Clinical trial, eyes with moderate to severe NPDR without CI-DME were randomized to receive 2.0 mg aflibercept or sham. Treatment was given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed.

Main outcomes measures

Development of CI-DME with vision loss or PDR.

Results

From 2016 to 2020, 328 participants (399 eyes) with moderate to severe NPDR without CI-DME were randomized to aflibercept injections (n = 200) or sham (n = 199). The 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs. 43.5% with sham. The 2-year cumulative probability of developing PDR was 13.5% in the aflibercept group vs. 33.2% in the sham, and the 2-year cumulative probability of developing CI-DME with vision loss was 4.1% in the aflibercept group vs. 14.8% in the sham group. The mean (SD) change in VA from baseline to 2 years was not significant, -0.9 (5.8) letters with aflibercept and -2.0 (6.1) letters with sham.

Limitations

20% loss of follow-up.

Conclusions

Eyes with moderate to severe NPDR treatment with periodic aflibercept decreased the development of PDR or vision-reducing CI-DME. However, through 2 years, preventive aflibercept did not confer VA benefit compared with observation plus treatment with aflibercept only after development of PDR or vision-reducing CI-DME.

Pearls for clinical practice

Eyes with moderate to severe NPDR can be observed and treated if required.